CN112870174A - Preparation method of telmisartan tablets - Google Patents

Abstract

The invention discloses a preparation method of telmisartan tablets, which comprises the following steps: adding an acid-base regulator into a solvent for full dissolution, adding telmisartan while stirring to perform a salt forming reaction until the solution is a light yellow transparent liquid, and then stirring and adding a crystallization inhibitor; fully dissolving and spray drying to prepare a solid dispersion; sieving the solid dispersion, and finishing; adding adjuvants, mixing, and making into tablet. Compared with the prior art, the tablet prepared by the preparation method can greatly improve the in-vitro dissolution rate and bioavailability of telmisartan, and ensure the stability of product quality.

Description

Preparation method of telmisartan tablets

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of telmisartan tablets.

Background

Telmisartan (Naringenin) is a specific angiotensin II receptor (AT1 type) antagonist, is combined with angiotensin II receptor AT1 subtype with high affinity, has lasting combination effect and long half-life, and can stably reduce blood pressure within the day after 1 tablet per day after being taken 1 time every day. Is the first choice medicine for treating essential hypertension. The medicine is particularly suitable for patients aged 55 years and older who have high risk of serious cardiovascular events and can not receive Angiotensin Converting Enzyme (ACEI) treatment, and can remarkably reduce the risk of death caused by myocardial infarction, stroke or cardiovascular diseases.

The chemical name is as follows: 4' -[ (1,4' -dimethyl-2 ' -propyl [2,6' -di-1H-benzimidazole)]-1' -yl) methyl]- [1,1' -Biphenyl group]-2-carboxylic acid, CAS registry number 144701-48-4, formula C₃₃H₃₀N₄O₂It has a molecular weight of 514.63 and has the following chemical structure:

telmisartan (trade name mecacarin) was first developed by the german briringer-bergahan company, first marketed in the united states in 1999, and introduced for sale in china at the end of 2000. The action mechanism of telmisartan for treating hypertension is as follows: selectively, difficult to reverse block angiotensin II binding to AT1 receptors in many tissues (e.g., vascular smooth muscle and suprarenal glands), thus blocking angiotensin II vasoconstriction and aldosterone secretion, resulting in a decrease in blood pressure without affecting other receptor systems in cardiovascular regulation. Because telmisartan has good antihypertensive effect, few adverse reactions and reliable curative effect, telmisartan is gradually developed into a first choice medicament for treating hypertension, and has the advantages of high bioavailability and long half-life compared with losartan and valsartan which are marketed at home.

However, telmisartan belongs to the class II in the BCS classification, and the telmisartan is generally not ideal in the aspects of in-vitro dissolution rate, bioavailability and product quality stability no matter prepared into tablets or capsule preparations. In addition, in the existing preparation method of telmisartan, a fluidized bed spray granulation process is adopted, and after drying is finished, the telmisartan is mixed with auxiliary materials and tabletted. The method has two granulation processes, and impurities can be introduced to influence the stability of the product. And the granules prepared by spray granulation have higher hardness and are not beneficial to absorption and utilization by human bodies.

Therefore, the development of a preparation method of temisartan tablets with high dissolution rate, good stability and simplified preparation steps is urgently needed.

Disclosure of Invention

In order to overcome the problems of low in-vitro dissolution rate and bioavailability, insufficient product quality stability and complicated preparation steps of telmisartan in the prior art, the invention provides a preparation method of telmisartan tablets.

The technical scheme adopted by the invention for solving the technical problems is as follows: the salifying and complex reaction technology is introduced to increase the solubility and release rate of the drug, thereby improving the bioavailability of the drug.

Another object of the present invention is to provide a telmisartan tablet prepared using the above method.

In order to achieve the above objects, the present invention provides a method for preparing telmisartan tablets, the method comprising:

adding an acid-base regulator into a solvent for full dissolution, adding telmisartan while stirring to perform a salt forming reaction until the solution is a light yellow transparent liquid, and then stirring and adding a crystallization inhibitor; fully dissolving and spray drying to prepare a solid dispersion; sieving the solid dispersion, and finishing; adding adjuvants, mixing, and making into tablet.

In a preferred embodiment, the solvent is selected from one or more of purified water, water for injection, ethanol;

the pH regulator is selected from one or more of meglumine, hydroxide, carbonate and bicarbonate;

the crystallization inhibitor is PVP-K30, and the mass ratio of telmisartan to PVP-K30 is 2.74: 1-4.10: 1;

the molar ratio of telmisartan to the pH regulator is 0.5: 1-1.5: 1.

Further, the solvent is purified water; the pH regulator is selected from meglumine and/or sodium hydroxide.

In a preferred embodiment, the conditions for the salt-forming reaction are: normal temperature and normal pressure, and the reaction time is as follows: 0.5 to 1 hour.

In a preferred embodiment, the parameters of the spray drying are:

the inlet air temperature is set to 130 +/-5 ℃, and the inlet air alarm deviation is as follows: 10 ℃;

liquid supply rotating speed: 50rpm plus or minus 10 rpm;

frequency of the induced draft fan: 40HZ plus or minus 1HZ, and the blower frequency is 23 plus or minus 1 HZ;

setting the back flushing time: 1.0 second, the back-flushing interval is set: 60.0 seconds;

rotating speed of the atomizer: 200 + -5 rps.

In a preferred embodiment, the mesh number of the screen is 20 to 60 mesh in the process of straightening the screen.

The telmisartan solid dispersion with superfine particle size can be prepared by limiting specific parameters of spray drying, and then the solid dispersion is screened by a screen to complete particles, so that the particle size of the solid dispersion is further limited; the telmisartan solid dispersion prepared by the technical parameters can be directly pressed into tablets after being added with auxiliary materials and mixed.

In a preferred embodiment, the mass ratio of all excipients to telmisartan is 0.05:1 to 10: 1.

Further, the auxiliary materials comprise a filler and/or a lubricant;

the filler is selected from one or more of sorbitol SI150, mannitol, lactose, PVP-K30, pregelatinized starch, dextrin, microcrystalline cellulose, hydroxypropyl cellulose, carboxymethyl starch sodium, etc.;

the lubricant is selected from one or more of stearate, silicon dioxide, sodium carboxymethyl starch, talcum powder, calcium phosphate, silicic acid or silicate.

In a preferred embodiment, the telmisartan tablet prepared by the preparation method is provided.

Compared with the prior art, the invention has the beneficial effects that:

1. the method adopts salification and composite reaction technologies, so that the problem of low solubility of telmisartan in the prior art is effectively solved, the dissolution rate is in direct proportion to the solubility of solid drugs according to a Noyes-Whitney dissolution rate equation, and the dissolution rate is improved by improving the solubility of telmisartan raw materials, so that the in-vitro dissolution rate and the bioavailability of telmisartan are improved.

2. The invention applies spray drying technology to prepare solid dispersoid of ultrafine particles, and directly adopts ultrafine dry powder to perform tabletting and pelletize. Replaces the common fluidized bed spray granulation in the prior art, can reduce the granulation process and prevent impurities from being mixed. In addition, the granules prepared by spray granulation in the prior art have higher hardness, and the dissolution rate and the bioavailability are obviously higher than those of the technical scheme of the invention.

Detailed Description

The present invention will be described in further detail below with reference to specific embodiments for better understanding of the present invention by those skilled in the art, but it should be understood that the scope of the present invention is not limited to the specific embodiments.

The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.

Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

Wherein the crystallization inhibitor is PVP-K30, and the purity requirement is as follows: k value is 27.0-32.0, pH is 3.0-7.0, aldehyde is less than or equal to 9.0ml, N-vinyl pyrrolidone is less than or equal to 3.5ml, and nitrogen content (calculated by anhydrous substance) is 11.6-12.8%;

the content of the telmisartan raw material is measured (by dry products) by 99.0-101.0 percent;

the content of the meglumine is measured (calculated by dry products) by 99.1 to 101.0 percent;

sorbitol SI150 content determination (by dry product) 98.2% -101.0%;

the content of the mannitol is measured (by anhydrous substance) to be 98.2-102.0%.

The embodiment of the application provides a preparation method of telmisartan tablets, and solves the problems that in the prior art, telmisartan is low in-vitro dissolution rate and bioavailability, product quality stability is insufficient, and preparation steps are complex. In the preparation process, an acid-base regulator is added into a solvent to be fully dissolved, telmisartan is added while stirring to perform salt forming reaction until the solution is a light yellow transparent liquid, and then a crystallization inhibitor is added while stirring; fully dissolving and spray drying to prepare a solid dispersion; sieving the solid dispersion, and finishing; adding auxiliary materials, mixing and pressing into tablets, can improve the in vitro dissolution and bioavailability of telmisartan, and ensures the stability of product quality.

In order to solve the above problems, the technical solution in the embodiment of the present application has the following general idea:

example 1

Adding 3.36g of sodium hydroxide into 200g of purified water under stirring for dissolving, slowly adding 12g of meglumine, stirring and fully dissolving, slowly adding 40g of telmisartan raw material under stirring, and stirring for 0.5-1.5 hours to enable a salt forming reaction to occur until the solution is light yellow transparent liquid; then, 12g of PVP-K30 was added with stirring to dissolve well in the liquid.

Spray drying the reactant to prepare a solid dispersion, and setting spray drying parameters: the air inlet temperature is set to be 130 +/-5 ℃, and the air inlet alarm deviation is as follows: 10 ℃; liquid supply rotating speed: 50rpm plus or minus 10 rpm; draught fan frequency: 40HZ plus or minus 1HZ, and the blower frequency is 23 plus or minus 1 HZ; setting the back flushing time: 1.0 second, the back-flushing interval is set as follows: 60.0 seconds; rotating speed of the atomizer: 200 + -5 rps.

After spray drying is finished, the prepared solid dispersion is screened by a 40-mesh screen to be sized, the particle size of the obtained solid dispersion is 40 meshes, then 16.86g of sorbitol SI150 and 0.4g of magnesium stearate are added, mixing is carried out for 20 minutes, and the prepared granules are tabletted to obtain 1000 telmisartan tablets with the specification of 40 mg.

In order to verify the improvement of the drug dissolution and bioavailability of the invention, we also quote two other preparation methods of the tablet and the comparison of the tablet prepared by the common method.

Comparative example 1:

after 40g of telmisartan, 32g of meglumine, 40g of mannitol, 15g of PEG6000, 25g of microcrystalline cellulose, 40g of pregelatinized starch, 12g of talcum powder, 5g of carboxymethyl starch sodium and 1g of magnesium stearate are uniformly mixed, direct tabletting is carried out, and the telmisartan tablet 1 with the specification of 40mg is prepared.

Comparative example 2:

after 40g of telmisartan, 32g of meglumine, 50g of mannitol, 95g of pregelatinized starch and 10g of PEG6000 are uniformly mixed, wet granulation is carried out by using a povidone K30 ethanol solution (povidone K30 is dissolved in 20-80% (V/V) ethanol to prepare 0.5-15% concentration (g/ml)), then drying is carried out in a decompression drying box at the temperature lower than 60 ℃, 5g of silicon dioxide, 12g of talcum powder, 5g of carboxymethyl starch sodium and 1g of magnesium stearate are added after granulation, and tabletting is carried out after uniform mixing, thus preparing the telmisartan tablet 2 with the specification of 40 mg.

Comparative example 3:

uniformly mixing 40g of telmisartan, 30g of microcrystalline cellulose, 100g of pregelatinized starch and 57g of dextrin, performing wet granulation by using a povidone K30 aqueous solution (povidone K30 is dissolved in purified water to prepare a concentration (g/ml) of 0.5-15%), drying in a reduced-pressure drying oven at the temperature lower than 60 ℃, adding 5g of silicon dioxide, 12g of talcum powder, 5g of carboxymethyl starch sodium and 1g of magnesium stearate after granulating, uniformly mixing, and tabletting to prepare the telmisartan tablet 3 with the specification of 40 mg.

Experimental example:

the telmisartan tablets prepared in the embodiment 1 of the invention and the telmisartan tablets prepared in the comparative examples 1 to 3 are subjected to in vitro dissolution and in vivo bioavailability comparative tests; in addition, the tablet prepared in example 1 of the present invention and the tablet prepared in comparative example 3 were examined for accelerated test and long-term stability test, respectively. The results are as follows:

dissolution rate comparison test:

taking 6 tablets of the product, and according to a dissolution determination method (second method of appendix XC of second part of 2010 edition of Chinese pharmacopoeia), using an RCZ-8B intelligent drug dissolution instrument produced by a wireless power plant of Tianjin university, wherein a device of the second method comprises a rotary paddle rod and a dissolution cup, and the deviation between the paddle rod and the vertical axis of the dissolution cup at any point during rotation is not more than 2 mm; the instrument is generally provided with 6 sets of measuring devices, and 6 tilmicosin tablets can be measured at one time. Dissolving phosphate buffer solution (PH7.5) (taking 13.6g of monopotassium phosphate, adding 800ml of water to dissolve, adjusting the PH value to 7.5 by using 2mol/l of sodium hydroxide solution, adding water to 1000ml, and shaking up to obtain 900ml of the solution) as a dissolving medium, rotating at 75 revolutions per minute, operating according to the method, taking a proper amount of the solution after 30 minutes, filtering, precisely taking 5ml (20mg specification) or 2ml (40mg specification) or 1ml (80mg specification) of the subsequent filtrate, placing the subsequent filtrate in a 10ml measuring flask, diluting the subsequent filtrate to a scale by using the dissolving medium, shaking up, and measuring absorbance at a wavelength of 296nm according to an ultraviolet-visible spectrophotometry (appendix IV A of the second part of Chinese pharmacopoeia 2010 edition); taking about 10mg of telmisartan reference substance, precisely weighing, placing in a 100ml measuring flask, adding 0.005mol/l sodium hydroxide methanol for dissolving and diluting to a scale, shaking uniformly, precisely weighing 5ml, placing in a 50ml measuring flask, diluting to the scale with a dissolution medium, shaking uniformly, measuring by the same method, and calculating the dissolution amount of each tablet. The limit is 80% of the indicated amount and should be met.

And (3) test results:

product(s)	Dissolution rate
		Tablets of the invention	99.6％
Tablet 1	81％
		Tablet 2	74％
Tablet 3	67％

The data show that the dissolution rate of the medicine prepared by the telmisartan tablet preparation method provided by the invention is obviously higher than that of a tablet preparation prepared by a common method.

(II) in vivo bioavailability comparative test

0.04g (40 mg/tablet X1 tablet) of telmisartan tablet of the present invention and 0.04g (40 mg/tablet X1 tablet) of 3 comparative telmisartan tablet formulations were randomly administered to 22 subjects alternately with warm water of 200 ml. Blood samples were collected at 0.33, 0.67, 1, 1.5, 2, 3, 5, 8, 12, 24, 48 hours before and after dosing, respectively, and the concentration of telmisartan in plasma was determined by the LC/MS method and the test data were processed by the 3P97 program, with the following data comparisons:

wherein the reference group has a trade name of

The specification was 40mg, and the manufacturer was Boehringer Ingelheim GmbH (Boehringer Ingelheim Pharma GmbH)&Co.KG)。

The data show that the bioavailability of the medicine prepared by the telmisartan tablet preparation method provided by the invention is almost consistent with that of a control group, and is obviously higher than that of a tablet preparation prepared by a common method. The relative bioavailability to the tablets even reaches 103%.

(III) comparative examination of stability

The tablet prepared by the preparation method provided by the invention and the tablet prepared by a common method are respectively subjected to accelerated experiment and long-term stability experiment investigation.

(1) Under the condition of accelerated experiment, a sample is placed in an intelligent constant temperature and humidity incubator with the temperature of 40 ℃ plus or minus 2 ℃ and the humidity of 75 percent plus or minus 5 percent for 6 months, the sample is taken for dissolution rate determination, and the sample is taken and analyzed at the end of 1 st, 2 th, 3 th and 6 th months in the intelligent constant temperature and humidity incubator for 6 months, and the effect is compared with the effect of 0 month, and the result is shown in the following table I.

Table one: comparative statistical table of investigation results of telmisartan tablet accelerated test (temperature 40 +/-2 ℃ and humidity 75% +/-5%)

(2) Under the long-term experimental conditions, the sample batches are placed in an intelligent constant-temperature constant-humidity incubator with the temperature of 25 +/-2 ℃ and the humidity of 60 +/-10%, sampled and analyzed in 3 rd, 6 th, 9 th, 12 th, 18 th, 24 th and 36 th months respectively, and compared with the effect of 0 month, the stability of the product is judged, and the results are shown in the following table two.

Table two: comparative statistical table of long-term test results (temperature 25 +/-2 ℃ and humidity 60% +/-10%) of telmisartan tablets

Compared to tablets prepared by conventional methods: after accelerated experiments and long-term test investigation, the quality indexes such as the content, the dissolution rate, related substances and the like of the prepared tablet have no obvious change; but the content of the tablets prepared by the common method is reduced, related substances are obviously increased and even exceed the standard, and the dissolution rate is obviously reduced by about 40-45%. The experimental result shows that the tablet prepared by the preparation method of the telmisartan tablet provided by the invention has no degradation and no obvious decrease in dissolution rate, and the quality of the sample is very stable.

Through the investigation of the three aspects, the preparation method of the telmisartan tablet provided by the invention can be well proved to effectively solve the problems of dissolution, bioavailability and product quality stability of the telmisartan tablet.

The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and its practical application to enable one skilled in the art to make and use various exemplary embodiments of the invention and various alternatives and modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.

Claims (10)

1. A method of preparing telmisartan tablets, the method comprising:

adding an acid-base regulator into a solvent for full dissolution, adding telmisartan while stirring to perform a salt forming reaction until the solution is a light yellow transparent liquid, and then stirring and adding a crystallization inhibitor; fully dissolving and spray drying to prepare a solid dispersion; sieving the solid dispersion, and finishing; adding auxiliary materials, mixing and pressing into the telmisartan tablets.

2. The preparation method according to claim 1, wherein the solvent is selected from one or more of purified water, water for injection, and ethanol;

the pH regulator is selected from one or more of meglumine, hydroxide, carbonate and bicarbonate;

the crystallization inhibitor is PVP-K30, and the mass ratio of telmisartan to PVP-K30 is 2.74: 1-4.10: 1.

The molar ratio of telmisartan to the pH regulator is 0.5: 1-1.5: 1.

3. The method according to claim 2, wherein the solvent is purified water.

4. The method of claim 2, wherein the pH modifying agent is selected from the group consisting of meglumine and sodium hydroxide.

5. The process according to claim 1, characterized in that the conditions of the salt-forming reaction are: normal temperature and normal pressure, and the reaction time is as follows: 0.5 to 1 hour.

6. The method of claim 1, wherein the parameters of spray drying are:

the inlet air temperature is set to 130 +/-5 ℃, and the inlet air alarm deviation is as follows: 10 ℃;

liquid supply rotating speed: 50rpm plus or minus 10 rpm;

frequency of the induced draft fan: 40HZ plus or minus 1HZ, and the blower frequency is 23 plus or minus 1 HZ;

setting the back flushing time: 1.0 second, the back-flushing interval is set: 60.0 seconds;

rotating speed of the atomizer: 200 + -5 rps.

7. The method according to claim 1, wherein the mesh number of the screen is 20 to 60 mesh in the process of finishing the granules.

8. The preparation method according to claim 1, wherein the mass ratio of all the auxiliary materials to telmisartan is 0.05: 1-10: 1.

9. The method of claim 8, wherein the excipient comprises a filler and/or a lubricant;

the filler is selected from one or more of sorbitol SI150, mannitol, lactose, PVP-K30, pregelatinized starch, dextrin, microcrystalline cellulose, hydroxypropyl cellulose, carboxymethyl starch sodium, etc.;

the lubricant is selected from one or more of stearate, silicon dioxide, sodium carboxymethyl starch, talcum powder, calcium phosphate, silicic acid or silicate.

10. Telmisartan tablets prepared according to the preparation method of any one of claims 1 to 9.